title: Mechanism of androgen receptor corepression by CKβBP2/CRIF1, a multifunctional transcription factor coregulator expressed in prostate cancer.
abstract: The transcription factor coregulator Casein kinase IIβ-binding protein 2 or CR6-interacting factor 1 (CKβBP2/CRIF1) binds the androgen receptor (AR) in prostate cancer cells and in response to dihydrotestosterone localizes with AR on the prostate-specific antigen gene enhancer, but does not bind DNA suggesting CKβBP2/CRIF1 localization in chromatin is determined by AR. In this study we show also that CKβBP2/CRIF1 inhibits wild-type AR and AR N-terminal transcriptional activity, binds to the AR C-terminal region, inhibits interaction of the AR N- and C-terminal domains (N/C interaction) and competes with p160 coactivator binding to the AR C-terminal domain, suggesting CKβBP2/CRIF1 interferes with AR activation functions 1 and 2. CKβBP2/CRIF1 is expressed mainly in stromal cells of benign prostatic hyperplasia and in stroma and epithelium of prostate cancer. CKβBP2/CRIF1 protein is increased in epithelium of androgen-dependent prostate cancer compared to benign prostatic hyperplasia and decreased slightly in castration recurrent epithelium compared to androgen-dependent prostate cancer. The multifunctional CKβBP2/CRIF1 is a STAT3 interacting protein and reported to be a coactivator of STAT3. CKβBP2/CRIF1 is expressed with STAT3 in prostate cancer where STAT3 may help to offset the AR repressor effect of CKβBP2/CRIF1 and allow AR regulation of prostate cancer growth.
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, University of North Carolina, School of Medicine, Chapel Hill, NC, United States.
authors.forename: Jiann-An
authors.initials: JA
authors.lastname: Tan
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, University of North Carolina, School of Medicine, Chapel Hill, NC, United States.
authors.forename: Suxia
authors.initials: S
authors.lastname: Bai
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, University of North Carolina, School of Medicine, Chapel Hill, NC, United States.
authors.forename: Gail
authors.initials: G
authors.lastname: Grossman
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Titus
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, School of Medicine, Chapel Hill, NC, United States.
authors.forename: O
authors.initials: O
authors.lastname: Harris Ford
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, United States.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Pop
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, United States.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Smith
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, United States; Lineberger Comprehensive Cancer Center, University of North Carolina, School of Medicine, Chapel Hill, NC, United States; Department of Urology, University of Buffalo, School of Medicine and Biotechnology, Buffalo, NY, United States.
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, University of North Carolina, School of Medicine, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina, School of Medicine, Chapel Hill, NC, United States; Department of Biochemistry and Biophysics, University of North Carolina, School of Medicine, Chapel Hill, NC, United States.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, University of North Carolina, School of Medicine, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina, School of Medicine, Chapel Hill, NC, United States. Electronic address: fsfrench@med.unc.edu.
authors.forename: Frank S
authors.initials: FS
authors.lastname: French
mesh_terms: D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002474:Cell-Free System; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000378:metabolism; D056970:Co-Repressor Proteins / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008024:Ligands; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: C410798:AR protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D056970:Co-Repressor Proteins; C476586:GADD45GIP1 protein, human; D008024:Ligands; C498001:NCOA2 protein, human; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013196:Dihydrotestosterone
keywords: Androgen receptor; Benign prostatic hyperplasia; Dihydrotestosterone; Prostate cancer; Protein kinase CK2 binding protein 2; Transcription coactivators and corepressors